BASIC RESEARCH
I Laboratory of Medical Investigation, LIM/08 (Anesthesiology), Faculdade
de Medicina da Universidade de São Paulo - São Paulo/SP, Brazil.
II Department of Surgery, Faculdade de Medicina Veterinária e Zootecnia
da Universidade de São Paulo - São Paulo/SP, Brazil.
III Department of Anesthesia and Surgical Intensive Care, Heart Institute
of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo/SP, Brazil.
Email: lim08@usp.br Tel: 55 11 3061-7293
Received for publication on December 09, 2009 First review completed on December 28, 2009 Accepted for publication on February 03, 2010
MINIMUM ALVEOLAR CONCENTRATIONS AND HEMODYNAMIC EFFECTS OF TWO
DIFFERENT PREPARATIONS OF SEVOFLURANE IN PIGS
Denise A. Otsuki,I Denise T. Fantoni,II Carla Holms,I Jose Otavio C. Auler Jr.III
doi: 10.1590/S1807-59322010000500011
Otsuki DA, Fantoni DT,Holms C, Auler-Junior JOC. Minimum alveolar concentrations and hemodynamic effects of two different preparations of sevolurane in pigs. Clinics. 2010(65)5:531-7.
BACKGROUND: Original sevolurane (Sevo A) is made with water, while a generic sevolurane (Sevocris) is produced with propylene glycol as a stabilizing additive. We investigated whether the original and generic sevolurane preparations differed in terms of their minimum alveolar concentration (MAC) values and hemodynamic effects.
METHODS: Sixteen pigs weighing 31.6±1.8 kg were randomly assigned to the Sevo A or Sevocris groups. After anesthesia in-duction via mask with the appropriate sevolurane preparation (6% in 100% oxygen), the MAC was determined for each animal. Hemodynamic and oxygenation parameters were measured at 0.5 MAC, 1 MAC and 1.5 MAC. Histopathological analyses of lung parenchyma were performed.
RESULTS: The MAC in the Sevo A group was 4.4±0.5%, and the MAC in the Sevocris group was 4.1±0.7%. Hemodynamic and metabolic parameters presented signiicant differences in a dose-dependent pattern as expected, but they did not differ between groups. Cardiac indices and arterial pressures decreased in both groups when the sevolurane concentration increased from 0.5 to 1 and 1.5 MAC. The oxygen delivery index (DO2I) decreased signiicantly at 1.5 MAC.
CONCLUSION: Propylene glycol as an additive for sevolurane seems to be as safe as a water additive, at least in terms of he-modynamic and pulmonary effects.
KEYWORDS: Inhalant anesthetics; Sevolurane; Minimum alveolar concentration; Pigs.
INTRODUCTION
Sevolurane is a luorinated hydrocarbon that stands out among today’s inhaled anesthetics due to its low solubility (blood: gas partition coefficient of 0.68), non-irritating effects on the respiratory tract and pleasant smell. These properties allow for rapid and smooth anesthesia induction even without pre-medication and offer good control over the depth of anesthesia, a factor that is important in patients with
compromised hemodynamic status.1
Depending on storage and usage conditions, sevolurane can be degraded into different compounds, including the highly pungent hydrofluoric acid, a substance known to be nephrotoxic and irritating to the respiratory tract mucous membrane. This sevoflurane decomposition reaction involves a metallic impurity, an acid (a Lewis acid) and a substance capable of receiving an electron pair to trigger the decomposition reaction. A number of compounds, both organic and inorganic, including H2O, butylated hydroxytoluene, methylparaben, propylparaben, propofol and thymol, can inhibit the Lewis acid reaction. A liquid additive (water) was developed as a stabilizer to the original sevolurane (Sevorane®, Abbott) to prevent the production of the inorganic luorides. Cristália Laboratories developed a new sevolurane formula (Sevocris, Cristalia,
São Paulo) containing 0.026% p/p of propylene glycol as a stabilizer.2 This new product was introduced into the
the approval of ANVISA, Brazil’s Regulatory Agency. Propylene glycol is a product utilized in several medications, via different routes, and has been considered a GRAS product (Generally Recognized as Safe) by the US Food and Drug Administration.3 It can be used as an antimicrobial
preservative, disinfectant, humectant, solvent, vitamin stabilizer and water-miscible co-solvent.
Given this information, we conducted a comparative study of sevoflurane with water additive versus with propylene glycol additive under experimental conditions in pigs. We compared the MAC, hemodynamic and metabolic effects and relevant lung histopathological analyses.
MATERIALS AND METHODS
The study protocol and design were approved by the Ethics and Animal Investigation Committee at our institution and were performed according to the recommendations of the National Institutes of Health guidelines for ethical animal research. Sixteen young male Large White x Landrace pigs weighing 30 to 35 Kg (31.6±1.8 Kg) were fasted overnight
with free access to water and were randomly assigned to the Sevo A or Sevocris groups. After induction of anesthesia via mask with the assigned sevolurane (6% in 100% oxygen), animals were orally intubated (7 mm internal diameter cuffed endotracheal tube, Hi-Lo, National Catheter, Argyle, NY). The lungs were mechanically ventilated (Primus, Dräger Medical, Lubeck, Germany) using volume-controlled ventilation, 40% FiO2, tidal volume of 8 mL/kg, PEEP of 5 cmH2O, which was the respiratory frequency adjusted to keep end-tidal CO2 between 35 and 45 mmHg. Anesthesia was maintained with 5% sevolurane in 40% oxygen.
A continuous infusion of lactated Ringer (Baxter, São Paulo, Brazil) was provided at a rate of 5 mL.kg-1.h-1
throughout all experiments. The temperature was maintained within normal limits for pigs (38.7-39.9°C) using warm blankets (Medi-therm II, Gaymar Industries, Orchard Park, NY, USA).
Instrumentation
After local anesthetic iniltration (10 mL 2% lidocaine with vasoconstrictor), the right femoral artery was surgically exposed and catheterized for arterial pressure measurements and blood collection. The right jugular vein was also catheterized with a pulmonary artery catheter (7.5 F Edwards CCO catheter connected to Edwards Vigilance CCO Monitor; Edwards Lifesciences Corp., Irvine, CA, USA). The position of the pulmonary artery catheter was conirmed by typical waveforms. All intravascular catheters were zeroed to atmospheric pressure. The midpoint between the
anterior and posterior chest walls was taken as the zero reference point for pressure measurements.
The STAT-Mode of the Edwards Vigilance CCO Monitor was used in each experiment, which displayed the actual cardiac output values registered over the past 60 seconds. The last ive measurements of CO were averaged. The electrocardiogram and intravascular pressures, mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP) and central venous pressure (CVP) were monitored continuously (MP40, Philips). Numerical values of intravascular pressures from the monitor screen were recorded at established points of the protocol. After instrumentation, animals were allowed to stabilize for 60 minutes.
Hemodynamic indices
The derivative indexes were recorded directly from monitors during the experiment: the pulmonary vascular resistance index (PVRI), systemic vascular resistance index (SVRI), right and left ventricular stroke work index (RVSWI and LVSWI), right stroke volume index, (RSVI), right ventricle ejection fraction (RVEF) and right ventricular end-diastolic volume (RVEDV). The cardiac index (CI) was calculated according to calculated body surface (k.BW2/3,
where k = 0.09, BW=body weight).4, 5
Venous admixture and oxygenation indices
Arterial and mixed venous blood samples were collected for pH, partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2), arterial oxygen saturation (SaO2), partial pressure of mixed venous oxygen (PvO2) and mixed venous saturation (SvO2) (ABL 555; Radiometer, Copenhagen, Denmark). The oxygen delivery index (DO2I), oxygen consumption index (VO2I) and extraction ratio (O2ER) were calculated utilizing conventional formulas.
Determination of MAC
The method for the determination of MAC in this study has been described elsewhere.6,7
decreased by 10%, and the protocol was repeated following a 15 min anesthetic equilibration period. If there was purposeful movement in response to the stimulation, the end-tidal concentration was increased by 5%, and following equilibration, the stimulation was repeated. The site of the stimulations was changed slightly to prevent sensitization or desensitization to subsequent stimuli. The expiratory concentration of the agent halfway between that allowing and that not allowing movement in response was the MAC of that agent for each speciic animal.
After MAC determination, systemic hemodynamics, respiratory data and blood gases were collected at 0.5, 1.0 and 1.5 MAC, observing a 15 min equilibrium period after each concentration change.
Histopathological analysis
At the end of the experiment, while still under anesthesia, animals received a 1-g bolus of thiopental followed by 25 mEq of potassium chloride. Lung samples were collected from the left diaphragmatic lobe (from zones 1, 2 and 3). A sample from the middle portion of the trachea was also collected. The lung and trachea samples were prepared for optical analyses, ixed in 10% formaldehyde and stained with hematoxylin and eosin.
The pathologist, who was blinded to the experimental protocol, described the analysis according to the combined assessment of neutrophils, eosinophils, mastocytes, and mononuclear cell accumulation, pulmonary interstitial edema, alveoli collapse, and congestion in the prepared sample lamina using an optical microscope at a magniication of 10x. In a subjective manner, the observer quantiied the positive indings in the samples from different regions of the lung as none (0), discrete (1), moderate (2), or intense (3).
Statistical analysis
MAC values were analyzed using the Student´s t-test.
Hemodynamic and other parametric data were analyzed within groups and between groups using an analysis of variance (ANOVA) for repeated measurements with two factors (SigmaStat 3.11, Systat Software Inc, San Jose, USA). When appropriate, post hoc analyses were performed with the Tukey test. P<0.05 was considered statistically signiicant. Values are presented as means (SD).
RESULTS
The MAC for the Sevo A group was 4.4% (0.5), whereas it was 4.1% (0.7) for the Sevocris group. Body weights,
MAC values and times to achieve sternal recumbence and to orotracheal intubation are presented in Table 1.
Hemodynamic, respiratory and oxygenation parameters are described in Tables 2 and 3.
Hemodynamic parameters presented significant differences in a dose-dependent pattern as expected, but did not differ between groups. Cardiac indices decreased signiicantly in both groups when the sevolurane concentration increased from 0.5 to 1 and 1.5 MAC. We also observed a significant decrease in blood pressure and mean pulmonary artery pressure at all concentrations compared to 0.5 MAC. Heart rate decreased signiicantly when MAC was augmented from 0.5 to 1.0 and 1.5, but the values remained in the physiological range for this group of animals, and bradycardia was not veriied. SvO2 and DO2I decreased signiicantly at 1.5 MAC when compared to 0.5 and 1.0 MAC.
Regarding histopathological analyses, no evidence of neutrophils, eosinophils, mastocytes, mononuclear cell accumulation, pulmonary interstitial edema, alveoli collapse, or congestion was found in lung optical microscopy of both groups. Also, no histopathological changes were found in the trachea.
DISCUSSION
The main inding in this study was that hemodynamic and metabolic responses at equipotent doses were similar between water-added sevolurane (Sevo A) and propylene glycol-added sevolurane (Sevocris).
Under the conditions of this study, the MAC of Sevo A was 4.4% (0.5), and the MAC of Sevocris was 4.1% (0.7). These values are higher than most published reports, in which sevolurane MAC values range between 2.1% and 4.4% in pigs.8-13
Several factors may account for the variations in published sevoflurane MAC values, including different age groups of pigs, body temperature, pre-anesthetic and induction agents, the type and site of noxious stimulus and the deined end-point for determination of purposeful
Table 1 - Body weight, MAC, time to sternal recumbency
and orotracheal intubation.
Sevo A Sevocris
Body weight (kg) 31.3 (1.9) 31.9 (1.9)
MAC (%) 4.4 (0.5) 4.1 (0.7) Sternal recumbency (s) 116 (96) 112 (36) Orotracheal intubation (s) 659 (433) 620 (275)
movement in response to the applied stimulus (Table 4). 6, 7, 14 The stimulus applied in our study was dewclaw clamping,
which has been reported to be a supramaximal stimulus6
and which remained constant during the entire study. The site of stimulus was changed slightly between stimulations to prevent sensitization or desensitization to subsequent stimuli. In the study of Hecker,10 where the pigs had almost
the same weight and were submitted to the same nociceptive stimulation as in the present study, the MAC was lower, which may have been due to the previous use of azaperone and propofol. Holmström and Åkeson,13 in animals weighing
20.1± 0.7 kg, obtained a MAC of 4.4 90 minutes after propofol administration, which is the same value reported in the present investigation. On the other hand, Moeser et al.,12 studying animals weighing 19 ±0.4 kg and with no
other agent than sevolurane, obtained a MAC of 3.5±0.17. In the present investigation, weight, age, sex, and stimuli were similar in both groups, demonstrating that the two
anesthetics showed the same behavior with regard to MAC. The hemodynamic results are close to those described in the literature for sevolurane. In healthy human volunteers and in dogs, the cardiac index, arterial pressure and pulmonary arterial pressure decrease in a dose-dependent manner.15,16 In infants, sevolurane did not alter the cardiac
index at any concentration compared to awake values but signiicantly decreased blood pressure and systemic vascular resistance compared to awake values at all concentrations.17
Special focus has been given to the effects of volatile anesthetics on heart rate because desflurane (and to a lesser extent isoflurane) can initiate major increases in heart rate that might predispose select patient populations to myocardial ischemia.18 The results with sevolurane are
conlicting, varying across different species, age groups and anesthetic techniques. Sevolurane has not been associated with increases in heart rate in healthy volunteers, in patients,19 or in children.17 Bernard et al.,16 in dogs, noted Table 2 - Hemodynamic data.
Group 0.5 MAC 1.0 MAC 1.5 MAC
CI (L/min/m2) Sevo A 5.5 (1.3) * 4.2 (0.8) 3.2 (1.0) * † Sevocris 6.2 (0.7) * 4.7 (1.1) 3.6 (1.2) * †
HR (beat/min) Sevo A 129 (20) 122 (17) 110 (16) * † Sevocris 138 (19) * 115 (15) 104 (13) † MAP (mmHg) Sevo A 81 (15) * 66 (7) 45 (10) * †
Sevocris 90 (17) * 68 (10) 52 (11) * †
CVP (mmHg) Sevo A 8 (2) 9 (2) 9 (2)
Sevocris 7 (2) * 9 (1) 10 (1) † MPAP (mmHg) Sevo A 23 (3) * 21 (2) 19 (3) * †
Sevocris 22 (3) * 21 (3) 20 (3) †
PAWP (mmHg) Sevo A 11 (2) 12 (2) 12 (1)
Sevocris 11 (1) 11 (1) 12 (2)
SVRI (dynes.sec/cm5/m2) Sevo A 1076 (211) 1106 (185) 896 (201) * † Sevocris 1080 (201) 1047 (260) 959 (193) PVRI (dynes.sec/cm5/m2) Sevo A 171 (34) 183 (30) 187 (61)
Sevocris 153 (35) 165 (41) 184 (63) LVSWI (gm-m/m2/beat) Sevo A 41 (12) * 26 (6) 13 (6) * † Sevocris 47 (13) * 33 (6) 20 (9) * †
RVSWI (gm-m/m2/beat) Sevo A 8 (2) * 6 (1) 4 (2) * † Sevocris 9 (1) * 7 (2) 5 (2) * †
SVI (mL/m2/beat) Sevo A 44 (9) * 34 (5) 28 (6) * † Sevocris 45 (6) 41 (8) 34 (9) * † EDVI (mL/m2) Sevo A 159 (33) 157 (52) 156 (58)
significant increases in heart rate from the awake state during the administration of 1.2-2.0 MAC. In the present study, heart rate decreased when the MAC was augmented from 0.5 to 1.0 and 1.5, but the values obtained remained in the physiological range for this group of animals, and bradycardia was not veriied.
The effects of both tested sevofluranes on cardiac
performance (LVSWI, RVSWI, SVI and EDVI) were the same and are in accordance with the literature. The inluence of sevolurane on performance of the right ventricle (RV) was studied by Kerbaul and colleagues, who observed a signiicant decrease in the RV stroke work with 1 and 1.5 MAC of sevolurane. 20
Ventilation was kept constant in order to maintain the
Table 3 - Respiratory and oxygenation data.
Group 0.5 MAC 1.0 MAC 1.5 MAC
RR (mpm) Sevo A 19 (2) 19 (2) 19 (2)
Sevocris 20 (2) 20 (2) 20 (2)
P Peak (cmH2O) Sevo A 22 (3) 21 (3) 21 (3)
Sevocris 20 (4) 20 (3) 20 (3) P Plato (cmH2O) Sevo A 20 (3) 20 (3) 20 (3)
Sevocris 19 (3) 19 (3) 19 (3) ComplDyn (mL/cmH2O) Sevo A 23 (5) * 26 (6) 27 (6) †
Sevocris 24 (5) 26 (4) 26 (5)
Vt (mL) Sevo A 339 (22) * 359 (29) 370 (39) * † Sevocris 335 (22) * 350 (28) 362 (22) * †
EtCO2 (mmHg) Sevo A 44 (2) 43 (2) 41 (2) * † Sevocris 44 (2) 43 (4) 41 (4) † pH art Sevo A 7.454 (0.024) 7.463 (0.026) 7.477 (0.025)
Sevocris 7.464 (0.024) 7.472 (0.041) 7.459 (0.060)
PaCO2 (mmHg) Sevo A 45 (2) 44 (3) 40 (5)
Sevocris 44 (2) 43 (5) 42 (8) PaO2 (mmHg) Sevo A 174 (36) 166 (40) 160 (43)
Sevocris 181 (20) 162 (27) 157 (33)
SaO2 (%) Sevo A 99.2 (0.5) 99.0 (0.5) 98.9 (0.9) Sevocris 99.4 (0.2) 99.1 (0.4) 99.0 (0.7) † Lactate (mmol/L) Sevo A 1.1 (0.3) 1.1 (0.3) 1.5 (1.0)
Sevocris 1.0 (0.2) 1.1 (0.3) 1.3 (0.3) PvO2 (mmHg) Sevo A 47 (5) 45 (6) 36 (5) * †
Sevocris 50 (3) * 45 (5) 38 (6) * † SvO2 (%) Sevo A 77.3 (7.3) 76.1 (7.3) 62.5 (14.7) * †
Sevocris 81.6 (3.9) 76.0 (6.2) 64.7 (12.4) * †
DO2I (mL/min/m2) Sevo A 825 (172) * 606 (56) 434 (96) * † Sevocris 880 (66) * 671 (176) 498 (156) * †
VO2I (mL/min/m2) Sevo A 173 (19) 142 (33) 143 (31) Sevocris 175 (22) 162 (32) 162 (12)
O2ER (%) Sevo A 23 (7) 24 (6) 35 (12) * †
Sevocris 20 (3) 25 (6) 36 (13)* † Temp (°C) Sevo A 38.3 (0.4) 38.4 (0.5) 38.5 (0.5) Sevocris 38.6 (0.6) 38.6 (0.4) 38.7 (0.5)
Table 4 - MAC (means±SD) results and methods employed in previous studies of pigs on sevolurane.
Reference Age
(weeks)
Weight (Kg)
Anesthesia protocol Nociceptive
stimulation
Temperature (°C)
MAC (%)
Lerman et al.8 newborn 2.1±0.4 mask induction hoof coronary ligament clamping
37.5-38.5 2.12±0.39
Allaouchiche et al. 9 12-14 23±2 after ketamine and propofol
dewclaw clamping
38.6±0.6 2.4
Hecker et al. 10 NS 30.8±2.6 3 h after azaperone, 45 min after propofol
dewclaw clamping
38.1 2.53±0.47
Manohar and Parks11 22-25 58.7±1.8 mask induction tail clamping 39.7±0.1 2.66±0.6 Moeser et al. 12 9 19±4 mask induction dewclaw clamping 38.1 3.5±0.17 Holmström and
Åkeson 13
NS 20.1±0.7 90 min after propofol
dewclaw clamping
38.0±0.2 4.4±0.1
NS=not stated.
levels of carbon dioxide, which may inluence cardiovascular function. The decreases in the oxygenation parameters, verified with the increases in MAC, may be associated with cardiovascular depression. The changes were more pronounced when MAC was raised to 1.5, contributing to a signiicant decrease in SvO2 and PvO2, while the oxygen extraction rate increased. Lactate remained unchanged with 1.0 MAC and increased slightly with 1.5.
No lung histopathological changes were associated with the two compositions of sevolurane tested. The literature describes how sevolurane may be degraded by metallic substances resulting in luoridric acid, which may cause damage to the respiratory tract mucous membrane when inhaled, and many other luoride-degrading products. To inhibit acid formation, substances such as water and, more recently, propylene glycol have been added to sevolurane. A test conducted with a sevolurane sample with 260 ppm of propylene glycol, heated to a temperature above 60°C in the presence of alumina, did not show signiicant change in the content of individual and total impurities when compared to those of the dry sevoflurane. The fluoride content of this sample was 0.051 µg/mL, which complied
with speciications set by the USP Pharmacopoeia Forum, which determines a maximum luoride limit of 2 µg/mL. 2
The exact mechanism through which propylene glycol stabilizes sevolurane is not entirely clear, but it is possible to infer that propylene glycol and the Lewis acid form a compound that is highly eficient for blocking the action of metallic impurities on sevolurane.
With regard to the possible toxicological effects of propylene glycol, hyperosmolality lactic acidosis, a central nervous system dysfunction, and cardiovascular disturbances were observed in patients receiving etomidate in a 35% propylene glycol vehicle.21, 22 In the present investigation, the
sevolurane contained 0.026% of propylene glycol, which is far less than the amount contained in etomidate formulation. Moreover, after a study conducted by Bau et al. in which propylene glycol was a constituent of an aerosol formulation, the authors concluded that, under normal conditions of exposure, propylene glycol via inhalation is of limited toxicological relevance.23
In conclusion, propylene glycol as a sevolurane additive can be used as safely as water as an additive, at least in terms of hemodynamic and pulmonary effects.
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